As the neurobiological mechanisms underlying emotional-affective disorders anxiety are emerging, critical roles are suggested for the amygdala and the neurotransmitter serotonin (5-hydroxytryptamine or 5-HT). However, the amygdala is also a common focus of excessive neuronal activity that manifests as temporal lobe epilepsy, and these patients may experience disturbed mood or anxiety. This suggests a link between emotion and epilepsy, and more specifically that excitability in the amygdala is important in controlling emotion. In evidence, some anticonvulsants also have mood-stabilizing properties. Mood and anxiety disorders may also involve low 5-HT levels since compounds acting on the 5-HT system are first-line treatments for many emotional disorders. Still, little is known about the cellular mechanisms of 5-HT in the amygdala. The purpose of this project is to examine the effects of low 5-HT in the amygdala on mechanisms controlling neuronal excitability in this important limbic area. The overall hypothesis is that low 5-HT in the amygdala leads to increased neuronal excitability that underlies pathological emotional behavior. Specifically, this project will determine if low 5-HT in the amygdala results in changes in fear behavior in vivo, and increases neuronal excitability in neurons of the lateral amygdala (LA) nucleus in vitro. We will determine the mechanism of action of low 5-HT-mediated changes in excitability of LA neurons and how this is involved in abnormal fear behavior. Preliminary studies show that 5-HT2 receptors are involved in the behavioral changes induced by low 5-HT, and that 5-HT2 receptors inhibit the hyperpolarization-activated current, IH, which regulates neuronal excitability. The specific aims of this application are to: (1) analyze the behavioral pharmacology of low-5-HT-induced changes in cued and contextual fear- conditioning in rats by intra-amygdala administration of 5-HT2 receptor ligands and the IH blocker ZD-7288; (2) define the physiological and pharmacological mechanisms involved in the 5-HT receptor control of IH using whole-cell recordings in brain slices containing the lateral nucleus of the amygdala. We will use an innovative and integrative approach that combines in vivo behavioral studies with in vitro physiology of amygdala neurons to gain important new information about the 5-HT-mediated mechanisms of excitability in the amygdala and the functional role of 5-HT2 receptors in fear behavior. By analyzing the cellular mechanisms of 5-HT in the amygdala and their functional role in fear behavior, this project may identify new targets involved in mood and anxiety disorders. This project will be accomplished at Baylor University, a primarily undergraduate institution where scientific research is an established priority. Award of this AREA grant will provide important resources necessary to help gifted students conduct original research as they prepare for careers in biomedical science. PUBLIC HEALTH RELEVANCE: Mood and anxiety disorders are a major public health concern since approximately 18% of the adult US population has an anxiety disorder, and 10% have a mood disorder. By understanding the biological substrates of fear and anxiety in an animal model of emotional behavior, this project may make a significant contribution to the well-being of people with mental illness by revealing new targets that contribute to symptoms of mood and anxiety disorders. [unreadable] [unreadable] [unreadable]